The present invention relates generally to renal nuclear matrix proteins, called "NMPs" here, and more specifically to novel nuclear matrix proteins of the kidney which are associated with cell-proliferative disorders.
U.S. Pat. Nos. 4,882,268 and 4,885,236, both issued to Fey and Penman, disclose certain NMPs and discuss their possible uses in identifying the origin of a tissue sample. In addition to identifying the origin of a tissue sample, the patents also discuss possible uses of NMPs to indicate certain disease states of a cell, such as viral infection, cancer, chromosomal defects or autoimmune disease. Specific NMPs discussed in the patents include those from human colon, lung, adrenal cortex and bladder cell lines.
The early diagnosis of renal cancer is central to the effective treatment of the disease. Currently, there are no methods available to easily and specifically identify the presence of renal cancer cells based on NMPs.
The nuclear matrix is the structural component of the nucleus that determines nuclear morphology, organizes the DNA in a three-dimensional fashion that is tissue specific, and has a central role in the regulation of a number of nuclear processes including the regulation of gene expression. The nuclear matrix has been demonstrated to play a central role in the regulation of important cellular processes such as DNA replication and transcription. Getzenberg, J. Cell Biochem. 55: 22-31 (1994). The nuclear matrix is the framework or scaffolding of the nucleus and consists of the peripheral laminas and pore complexes, an internal ribonucleic protein network, and residual nucleoli. Berezney et al., Biochem. Biophys. Res. Comm. 60: 1410-17 (1974). The nuclear matrix consists of approximately 10% of the nuclear proteins and is virtually devoid of lipids, DNA and histones. Fey et al., Crit. Rev. Eukaryotic Gene Expression 1: 127-44 (1991).
A majority of the known NMPs are common to all cell types and physiologic states. A number of laboratories have identified NMPs which may be unique to certain cell types or states. Mitogenic stimulation and the induction of differentiation have been demonstrated to alter the composition of nuclear matrix proteins and structure. The nuclear matrix contains a number of associated proteins that have been demonstrated to be involved in transformation. Berezney first showed that the nuclear matrix is altered in transformation, examining hepatoma nuclear matrix proteins. Berezney et al., Cancer Res. 39: 3031-39 (1979). Fey and Penman demonstrated that tumor promoters induce a specific morphologic signature in the nuclear matrix-intermediate filament scaffold of kidney cells. Fey et al., Proc. Nat'l Acad. Sci. USA 81: 859-66 (1984). Fey and Penman went on to demonstrate that the pattern of NMPs differed between normal and tumorigenic cell lines. Fey et al., loc. cit. 85: 121-25 (1989). An antibody to a nuclear matrix protein, termed NM-200.4, was raised from the breast carcinoma cell line T-47D. Weidner et al., Am. J. Path. 138: 1293-98 (1991). This antibody reacts strongly with human breast carcinoma specimens as well as specimens from lung, thyroid, and ovarian cancers, but does not react with normal epithelial cells of similar origin, raising the possibility of the use of certain anti-NMP antibodies as diagnostic tools.
Exposure of canine kidney cells to various tumor promoters has also been found to alter the nuclear matrix-intermediate filament organization in these epithelial cells. Fey et al., Proc. Nat'l Acad. Sci. USA 81: 4409-4413 (1984).
It has been demonstrated with the Dunning rat model of prostate cancer that nuclear matrix protein composition is altered when comparing the normal dorsal prostate with the spontaneously arisen rat prostate adenocarcinomas. In U.S. Pat. No. 5,849,509, the entire contents of which are incorporated by reference herein, when human prostate samples were examined, nuclear matrix proteins were identified that (1) were present only in the normal prostate and were missing in both prostate cancer and benign prostatic hyperplasia (BPH) (normal pattern), (2) were found only in the prostate cancer cells and missing in the normal prostate and BPH (prostate cancer pattern), and (3) were found in both normal and BPH samples but were absent from prostate cancers.
In co-pending U.S. application Ser. No. 08/742,850 (now U.S. Pat. No. 5,866,535), the entire contents of which are incorporated by reference herein, NMPs are disclosed which are present only in normal bladder cells and are absent in bladder cancer cells. Also, the application discloses other NMPs that are found only in bladder cancer cells but are absent in normal bladder cells.
No nuclear matrix proteins have been isolated heretofore, however, that are linked specifically to renal cancer.